Neonatal rat hypoxia-ischemia: Effect of the anti-oxidant mitoquinol, and S-PBN.
BACKGROUND
The production of oxygen free radicals after perinatal hypoxia-ischemia is thought to play a critical role in the pathogenesis of the brain injury. Administration of anti-oxidants may thus be neuroprotective. The aim of the present study was to investigate the effect of a mitochondria-targeted anti-oxidant mitoquinol (mitoQ) administered in the form of the prodrug mitoquinone, and an extracellular anti-oxidant N-tert-butyl-(2-sulfophenyl)-nitrone (S-PBN; Aldrich, St Louis, MO, USA), on neuronal survival in the rat striatum after acute perinatal hypoxia-ischemia.


METHODS
Mitoquinone at 17 micromol/L (n = 6) or 51 micromol/L (n = 6), or its diluent (n = 12), was continuously infused over 3 days into the right striatum of Sprague-Dawley rats. Infusion was via an Alzet micro-osmotic pump (Alza, Los Angeles, CA, USA), stereotaxically implanted on postnatal day (PN) 7 under anesthesia. In another experiment, S-PBN (100 mg/kg) (n = 8) or its diluent (n = 8) was administered in six s.c. injections every 12 h from the evening of PN7. Hypoxia-ischemia was induced on PN8 by right common carotid artery ligation under anesthesia, followed 2.5 h later by exposure to 8% oxygen for 1.5 h. On PN14 the pups were euthanased and 40 microm serial sections were cut through the entire striatum. The total number of medium-spiny neurons within the right striatum was stereologically determined using the optical disector/Cavalieri method.


RESULTS
No significant difference was seen in the total number of striatal medium-spiny neurons between the 17 micromol/L or 51 micromol/L mitoQ-treated pups and their respective diluent-treated controls. No significant difference was seen in the total number of striatal medium-spiny neurons between the S-PBN-treated and diluent-treated pups.


CONCLUSIONS
Solely targeting mitochondrial oxidants with mitoQ, or extracellular oxidants with S-PBN, is not protective for striatal medium-spiny neurons after perinatal hypoxia-ischemia.
Hobbs
Catherine E
CE
Department of Anatomy and Structural Biology, University Otago, Dunedin, New Zealand.
Murphy
Michael P
MP
Smith
Robin A J
RA
Oorschot
Dorothy E
DE
D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000494:pharmacology*; D001557:Benzenesulfonates / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology; D020925:Hypoxia-Ischemia, Brain / Q000473:pathology*; D009474:Neurons / Q000187:drug effects; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014451:Ubiquinone / Q000494:pharmacology* / Q000031:analogs & derivatives
D000975:Antioxidants; D001557:Benzenesulfonates; D009943:Organophosphorus Compounds; C094272:N-tert-butyl-(2-sulfophenyl)nitrone; D014451:Ubiquinone; C429014:mitoquinone; C429015:mitoquinol